Nerve abnormalities in lumbar disc herniation: A systematic review and meta-analysis of diffusion tensor imaging

Purpose The purpose of this study was to examine the values of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) in diffusion tensor imaging (DTI) for diagnosing patients with nerve impairment due to lumbar disc herniation (LDH). Methods A literature search of databases (PubMed, Web of Science, Cochrane Library and Embase) was systematically performed to identify articles published before September 2021 that were relevant to this study. FA and ADC estimates of compressed nerve roots due to LDH and healthy controls in the same segment were compared, with either fixed or random effects models selected according to I2 heterogeneity. Additionally, subgroup analysis, sensitivity analysis, potential publication bias analysis and meta-regression analysis were also performed. Results A total of 369 patients with LDH from 11 publications were included in this meta-analysis. The results showed significantly lower FA values (Weighted Mean Difference (WMD): -0.08, 95% confidence interval (CI): -0.09 to -0.07, P ≤ 0.001, I2 = 87.6%) and significantly higher ADC values (WMD: 0.25, 95% CI: 0.20 to 0.30, P ≤ 0.001, I2 = 71.4%) of the nerve on the compressed side due to LDH compared to the healthy side. Subgroup analysis indicated that different countries and magnetic field strengths may be associated with higher heterogeneity. Furthermore, meta-regression analysis further revealed that segment and field strength did not have a significant effect on the results, regardless of the FA or ADC values. Contrastingly, in FA, the year of publication, country, b value and directions showed an effect on the results. Conclusions This meta-analysis showed a significant decrease in FA and a significant increase in ADC in patients with nerve damage due to LDH. The results favourably support the presence of nerve impairment in patients with LDH.


Introduction
Lumbar disc herniation (LDH) is clinically characterized by sciatica and low back pain (LBP), which severely affect the quality of life and impose a serious burden on the healthcare system and patients' families [1,2]. Sciatica is caused by the compression of the sciatic nerve with a herniated intervertebral disc. Additionally, epidemiological investigations have reported that LDH is the most common cause of nerve root compression in the lumbosacral region [3]. The main signs and symptoms of LDH include rhizomatic pain, hyperalgesia and incompetence in the circulation of a nerve root in one or more lumbosacral regions [4]. Magnetic resonance imaging (MRI) is the standard indicator for evaluating LDH, with high accuracy and reliability rates [5]. Although conventional MRI is widely used clinically, it is difficult to assess the severity of nerve root compression based solely on an MRI [6]. Clinicians may observe symptoms that are significantly inconsistent with the imaging findings. Patients without significant nerve root compression on imaging may have severe clinical signs of nerve root compression whereas those with severe compression may not have significant clinical signs. Additionally, patients with untreated herniated lumbar discs may also exhibit complex clinical symptoms. Therefore, it can be hypothesised that the mechanical compression of the lumbar disc on MRI is not the only cause of low back pain and sciatica in patients.
Diffusion tensor imaging (DTI) is a proven functional magnetic resonance imaging (fMRI) technique, which reflects the internal microstructural characteristics of tissues more accurately than other MRIs by calculating the anisotropy of water molecule diffusion in tissues. This technique is currently widely used in various fields; however, it is mainly used in the evaluation of central nervous system lesions [7], peripheral nervous system lesions [8], spinal cord lesions [9], intracranial vascular diseases [10] and other nerve-related diseases. Apparent dispersion coefficient (ADC) and fractional anisotropy (FA) are two important parameters of DTI in the observation of nerve lesions. FA measures the directionality of spreading and details the integrity of the fibres while ADC reflects the diffusivity of molecules in 3D tissue space [11]. Moreover, the degree of nerve root compression has been correlated with FA and ADC values [3]. The higher the degree of nerve root compression, the lower the FA value and the higher the ADC value. Therefore, FA and ADC values can reflect the pathophysiological state of nerve fibre bundles caused by LDH [12].
Previous studies have reported encouraging results regarding the use of DTI in the diagnosis of nerve injury due to LDH; however, variations exist in DTI values across segments and with different degrees of compression. Additionally, various factors such as magnetic field strength, measurement technique, scanning parameters and position choice can vary the sensitivity of the DTI results [13][14][15]. Several studies have also reported that FA values are generally decreased after a herniated disc compresses a nerve [14,16,17]. However, it remains controversial whether ADC values increase after a nerve injury [18,19]. Consequently, this review demonstrates the importance of ADC and FA values in DTI in the diagnosis of nerve compression due to LDH. This systematic meta-analysis is divided into two main aspects. The first aspect clarifies the changes in the DTI parameters (mainly FA and ADC values) of the nerve on the compressed side compared to the healthy side. The second aspect uses meta-regression to explore the effects of publication year, study country nerve root compression segment and scanning parameter settings on DTI outcomes.

Literature search and data sources
This study was designed and reported following the PRISMA Declaration Guidelines [20]. Studies in the PubMed, Web of Science, Cochrane library and Embase database were searched using the following search terms: 'Diffusion tensor imaging', 'DTI', 'Imaging, Diffusion Tensor', 'Diffusion Tensor MRI', 'Diffusion Tensor MRIs', 'MRI, Diffusion Tensor,' 'DTI MRI', 'Diffusion Tractography', 'Tractography, Diffusion', 'lumbar disc herniation', 'LDH', 'lumbar disc protrusion', 'lumbar disk herniation', 'lumbar herniated disk', 'lumbar intervertebral disc herniation', 'lumbar intervertebral disc prolapse' and 'prolapse of lumbar intervertebral disc.' Articles published before September 2021 were retrieved. Furthermore, two reviewers independently screened the titles and abstracts of the research studies to ensure precise results. The search results were imported to EndNote X9 software for further treatment (Table 1).

Inclusion and exclusion criteria
Inclusion criteria were as follows: (1) studies reporting DTI indexes in patients with LDH who have FA or ADC values on the affected side versus healthy controls; (2) diagnosis of LDH with nerve compression based on patient symptoms, signs and imaging; (3) original clinical articles. Exclusion criteria were as follows: (1) unclear expression of the measurement methods of FA and ADC values; (2) incomplete information; (3) missing data; (4) case reports, duplicate literature and studies using animals as study subjects.

Data extraction and quality assessment
Two authors independently performed a quality assessment of the included literature, extracting essential information and data for analysis. Disagreements were resolved by consensus after discussion, and if still controversial, a third reviewer was introduced to join the discussion. Demographic characteristics (age, sample size, country, gender), clinical data (prominent segments), indicators of measurement and imaging parameters were extracted (Tables 1 and  2), and the quality of the included literature was evaluated according to Newcastle-Ottawa Scale (NOS) [21].

Statistical analysis
Stata 14 software was used for quantitative merging. Weighted Mean Difference (WMD) values and 95% confidence interval (CI) were used as the combined effect indicators, and the chi- square test combined with the I 2 indicator was used to test the heterogeneity of the included studies. P < 0.1 and I 2 > 50% indicated heterogeneity between studies, and the random-effects model was used; however, P � 0.1 and I 2 � 50% indicated no significant heterogeneity between studies, and the fixed effect model was used. Sensitivity and subgroup analyses were used to find the possible sources of heterogeneity. Publication bias was assessed by observing the symmetry of the funnel plot and Egger's graph. The effect of multiple variables on outcome was evaluated using meta-regression analysis. Additionally, inter-rater reliability and Cohen's kappa were used for quality assessment.

Included studies
A total of 11 English-language publications, including 369 patients with LDH, were included in this meta-analysis, and the literature search process and results are shown in Fig 1. FA values were reported in all 11 studies included in the meta-analysis, but ADC values were reported in only eight studies. The characteristics of all general studies and imaging parameters included in the literature are shown in Tables 2 and 3, respectively. The results of the literature quality assessment using the NOS tool are shown in Table 4.

Meta-analysis of LDH induced DTI changes(FA and ADC values)
A meta-analysis of FA values in the included studies revealed that the nerve compression side of patients with LDH had significantly lower FA values compared to the healthy side (WMD: -0.08, 95% CI: -0.09 to -0.07, P � 0.001, I 2 = 87.6%; Fig 2A). However, the eight publications reporting ADC values showed significantly higher values on the affected side of patients with LDH compared to the healthy side (WMD: 0.25, 95% CI: 0.20 to 0.30, P � 0.001, I 2 = 71.4%; Fig 2B). Moreover, owing to the high heterogeneity of the model, a random effects model was used for subsequent analysis.

Subgroup analyses
Owing to the high heterogeneity in this study, the origin of heterogeneity was evaluated using subgroup analysis, focusing primarily on magnetic field strength. Subgroup analysis revealed that patients with LDH had significantly lower FA values on the affected side than on the healthy side(1.5T: WMD: -0.07, 95% CI: -0.11 to -0.03, P � 0.001, I 2 = 96.2%; 3.0T: WMD: -0.08, 95% CI: -0.09 to -0.07, P � 0.001, I 2 = 74.3%)( Fig 3A). However, based on field strength, subgroup analyses revealed that patients with LDH had significantly higher ADC values on the affected side than on the healthy side (1.5T: WMD: 0.29, 95% CI: 0.21 to 0.36, P = 0.047, I 2 = 67.2%; 3.0T: WMD: 0.22, 95% CI: 0.16 to 0.29, P = 0.003, I 2 = 70.1%) ( Fig 3B). These results suggest that magnetic field strength, although it has some influence on heterogeneity, is not the primary reason for the higher heterogeneity in this study. Moreover, the results of the subgroup analysis are consistent with that of the meta-analysis.

Publication bias
The funnel plots for FA ( Fig 4A) and ADC (Fig 4B) show a possible risk of publication bias in this study. As can be seen in the figures, although the funnel plot for FA is slightly symmetrical, there is missing data in the lower half of the overall, as well as in the lower right corner of ADC. To test the asymmetry of the funnel plot, we also performed an Egger's test. Furthermore, Egger's graph shows that the FA (Fig 5A)

Sensitivity analysis
Sensitivity analysis revealed that both FA ( Fig 6A) and ADC (Fig 6B) showed good robustness in this study.

Meta-regression analysis
Data from the included publications were used for meta-regression analysis. The variables including the year of publication, country, compression segment, b vale, field strength and directions in the study were used to clarify whether these factors affected the results of this review. Meta-regression analysis of FA values demonstrated that the P values of the publication year, country, b value and directions were less than 0.05 (Table 5), indicating the effect of these variables to a certain extent on the results of ADC. Furthermore, we also performed a metaregression analysis of these six factors in the study of ADC values. The results of the metaregression of ADC values showed that the p-values were greater than 0.05 for all included factors ( Table 6), indicating that there was no significant effect of these factors on the results of ADC.

Discussion
LDH is a common cause of lumbar and sacral nerve compression and has a high clinical incidence, severely affecting the physical and mental health of patients. Although conventional

PLOS ONE
Diffusion tensor imaging MRI can determine if a herniated disc is compressing the nerve root, it cannot determine the extent of damage and the intrinsic structure of the nerve root after compression. However, an electromyogram (EMG) can be used to examine the nerves in the compressed nerve root area; however, it can prove to be traumatic for the patient and psychological factors can partially influence the results [30]. Thus, DTI has been introduced for the assessment of nerve injury due to LDH. The FA and ADC values commonly employed in DTI can be applied to measure the degree of nerve damage caused by LDH and have been widely used in clinical practice recently [14,17,25,26]. Furthermore, a significant correlation between FA and ADC values and clinical symptoms has been reported. Studies also show that higher Japanese Orthopaedic Association (JOA) scores were associated with higher FA and lower ADC values, and lower Roland-Morris Disability Questionnaire (RDQ) scores were associated with higher FA and lower ADC values [31]. Moreover, pre-operative or post-operative symptom improvements were also accompanied by changes in DTI values [19,32]. These studies reveal that DTI is an essential tool for the assessment of neurological abnormalities due to LDH as it can not only pinpoint the location of the nerve root compression for clinical reference before surgery but also complement the severity of clinical symptoms to achieve a higher degree of disease assessment. Additionally, it can also assess postoperative nerve recovery without causing adverse effects. Thus, a meta-analysis of DTI on the compressed and healthy sides of patients with LDH is necessary to demonstrate the validity of fMRI techniques in the diagnosis of nerve injury caused by LDH.
To the best of our knowledge, this meta-analysis is the first to perform a quantitative diagnosis of nerve root compression due to LDH using DTI. While assessing neurological status, the representative indicators are FA values and ADC values [8]. Thus, we focused on the changes in these indicators on the compressed and healthy sides using DTI. The results revealed nerve damage to some extent after the compression of the nerve by a herniated disc, with the affected side showing a decrease in FA values and an increase in ADC values compared to the healthy side via DTI analysis. This indicates the potential of DTI in the clinical assessment of the degree of nerve root damage due to LDH. The sensitivity of DTI detection is influenced by many factors, including population type, compression segments, age, gender, countries, MRI parameters and others [3]. Hence, to reduce the bias of the results due to demographic characteristics, the healthy side of the same segment in the same patient was selected as a control in this study.
To further investigate the source of heterogeneity, subgroup analysis was performed based on the varying field strength. The results showed that for FA value, the I 2 value of 1.5T increased to 96.2% while that of 3.0T decreased to 74.3%; for ADC value, the I 2 value of 1.5T decreased to 67.2%, while that of 3.0T decreased to 70.1%. This suggests that different field strengths could lead to high heterogeneity of DTI measurement results. With the continuous development of imaging technology, 3.0T is gradually replacing 1.5T in clinical use owing to its higher definition. Nonetheless, 3.0T MRI is now mostly used for the diagnosis of nerve injury [33]. Nevertheless, our results showed that although the strength of the magnetic field leads to an increase in heterogeneity, the subgroup analysis reveals that the results obtained support the conclusions of this study, regardless of whether it is 1.5T or 3.0T. Additionally, there exist certain differences in the conventional parameter settings of DTI in the included literature, including b-value, directions, TE, TR, FOV, Matrix and other variables. Different parameter settings have varying effects on the results of neurological measurements; therefore, it is vital to set an appropriate and reasonable reference range.
Meta-regression analysis further revealed that segment and field strength did not have a significant effect on the results, regardless of the FA or ADC values. Contrastingly, in FA, there may be some effect of year of publication, country, b value and directions on the results, which may be related to the fact that there are more values of them and less literature included. However, the small size of included literature makes the meta-regression results less robust.
Various clinical studies have demonstrated a reduction in FA values on the damaged side of the nerve whereas the ADC values remain controversial [19,25,31,34,35]. For instance, Wu et al. [19] found no statistically significant difference in ADC values between the compressed lateral nerve and the contralateral nerve root at the same stage (P = 0.517). ADC values mainly respond to the ability of water molecules to diffuse in the tissues. When nerve compression is significant, various factors lead to nerve oedema, myelin lysis, axonal swelling and subsequently increased diffusion of water molecules inside and outside the nerve, ultimately leading to an increase in ADC values [16,19,27,35,36]. Furthermore, Zhang et al. [14] reported a moderate negative correlation between nerve root compression severity for FA (r = -0.646, P < 0.01) and a positive correlation for ADC (r = 0.408, P < 0.01). However, it has been speculated that ADC values might not change significantly when there is a lack of oedema, inflammatory lesions and demyelination of the nerve root [12]. The results of our meta-analysis show that when lumbar disc herniation causes nerve compression, the decrease in FA values of the nerve on the compressed side is clear and an increase in ADC values is observed, which can serve as a reference in clinical practice.

Limitation
This study has certain limitations. First, the number of studies included was less and although certain conclusions were drawn, the results still lack robustness. Second, the heterogeneity of this article is high, and although subgroup analysis and heterogeneity tests were conducted, the main cause of heterogeneity remains unknown. Third, some of the extracted data were incomplete and some higher-quality documents were excluded because of the lack of primary data. Fourth, DTI detection is influenced by various factors. Although subgroup analysis analysed the magnetic field strength, the small sample size makes the results less reliable. Moreover, various interference factors in the parameters of DTI need to be unified and coordinated to better and more accurate results. Additionally, this article could not obtain a PROSPERO registration number in time; however, this overlook will be rectified soon. Furthermore, the samples included in the literature are small sample studies; therefore, further validation is required using a large sample and multicentric studies.

Conclusions
This study demonstrated that DTI is essential for the non-destructive assessment of the operational status of nerves compressed by LDH. The nerve on the compressed side showed a significant decrease in FA values and an increase in ADC values compared to the healthy side via DTI. Thus, the diagnosis of nerve damage due to LDH using DTI is confirmed to be accurate. This mode of testing can be used as a reference in clinical practice.